Inclusion complexes require higher concentration of Beta cyclodextrins (βCD) resulting in increased formulation bulk, toxicity, and production costs. This systematic review offers a comprehensive analysis using Quality by design (QbD) as a tool to predict potential applications of Polyvinylpyrrolidone (PVP) as a ternary substance to address issues of inclusion complexes. We reviewed 623 documents from 2013 to 2023 and Eighteen (18) research papers were selected for statistical and meta-analysis using the QbD concept to identify the most critical factors for selecting drugs and effect of PVP on inclusion complexes. The QbD analysis revealed that Molecular weight (MW), Partition coefficient (Log P), and the auxiliary substance ratio directly affected complexation efficiency (CE), thermodynamic stability in terms of Gibbs free energy (ΔG), and percent drug release. However, Stability constant (Ks) remained unaffected by any of these parameters. The results showed that low MW (250), median Log P (6), and a βCD: PVP ratio of 2:3 would result in higher CE, lower G, and improved drug release. PVP improves drug solubility, enhances delivery and therapeutic outcomes, and counteracts increased drug ionization due to decreased pH. In certain cases, its bulky nature and hydrogen bonding with CD molecules can form non-inclusion complexes. The findings of the study shows that there is potential molecular interaction between PVP and β-cyclodextrins, which possibly enhances the stability of inclusion complexes for drug with low MW and log P values less than 9. The systematic review shows a comprehensive methodology based on QbD offers a replicable template for future investigations into drug formulation research.

Olmesartan medoxomil (OLM) is a selective angiotensin II receptor antagonist used in the treatment of hypertension. Its therapeutic potential is limited by its poor water solubility, leading to poor bioavailability. Encapsulation of the drug substance by two methylated cyclodextrins, namely randomly methylated β-cyclodextrin (RM-β-CD) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TM-β-CD), was carried out to overcome the limitation related to OLM solubility, which, in turn, is expected to result in an improved biopharmaceutical profile. Supramolecular entities were evaluated by means of thermoanalytical techniques (TG-thermogravimetry; DTG-derivative thermogravimetry), spectroscopic methods including powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) and UV spectroscopy, saturation solubility studies, and by a theoretical approach using molecular modeling. The phase solubility method reveals an AL-type diagram for both inclusion complexes, indicating a stoichiometry ratio of 1:1. The values of the apparent stability constant indicate the higher stability of the host-guest system OLM/RM-β-CD. The physicochemical properties of the binary systems are different from those of the parent compounds, emphasizing the formation of inclusion complexes between the drug and CDs when the kneading method was used. The molecular encapsulation of OLM in RM-β-CD led to an increase in drug solubility, thus the supramolecular adduct can be the subject of further research to design a new pharmaceutical formulation containing OLM, with improved bioavailability.

In this work, comprehensive ab initio quantum chemical calculations using the DFT level of theory were performed to characterize the stabilization interactions (H-bonding and hyperconjugation effects) of two stable symmetrical conformations of α-, β-, and γ-cyclodextrins (CDs). For this purpose, we analyzed the electron density using \"Atom in molecules\" (AIM), \"Natural Bond Orbital\" (NBO), and energy decomposition method (CECA) in 3D and in Hilbert space. We also calculated the H-bond lengths and OH vibrational frequencies. In every investigated CD, the quantum chemical descriptors characterizing the strength of the interactions between the H-bonds of the primary OH (or hydroxymethyl) and secondary OH groups are examined by comparing the same quantity calculated for ethylene glycol, α-d-glucose (α-d-Glcp) and a water cluster as reference systems. By using these external standards, we can characterize more quantitatively the properties of these bonds (e.g., strength). We have demonstrated that bond critical points (BCP) of intra-unit H-bonds are absent in cyclodextrins, similar to α-d-Glcp and ethylene glycol. In contrast, the CECA analysis showed the existence of an exchange (bond-like) interaction between the interacting O…H atoms. Consequently, the exchange interaction refers to a chemical bond, namely the H-bond between two atoms, unlike BCP, which is not suitable for its detection.

Phenolic acids are phytochemicals commonly existing in plants that are also beneficial to the human body after consumption. As additives in the food industry, phenolic acids typically need stabilization by encapsulation. We have been studying cyclodextrins as potential encapsulating agents, elucidating the structure and energetics of the complexes they form with phenolic acids. To highlight the role of the solvent in these interactions and to investigate the possible component ratios available to these complexes, we first carried out gas-phase studies monitored through mass spectrometry that allowed us to work in solvent-free conditions. In addition to detecting the products of these complexation equilibria qualitatively, we were also able to find conditions to quantitative determine the relative binding affinities associated with these processes. As well as on the unusual complex stoichiometry observed in the gas phase for a series of phenolic acids with α-CD, β-CD, and γ-CD. We propose an explanation of these uncommon stoichiometries through solvation effects involving the cyclodextrin host as the solvating species. We also report on the observed trends in the measured relative affinities of these interactions.

The characteristic alkaloid component of the leaves of the catnip shrub (Catha edulis) is cathinone, and its synthetic analogs form a major group of recreational drugs. Cathinone derivatives are chiral compounds. In the literature, several chiral methods using cyclodextrins (CDs) have been achieved so far for diverse sets of analogs; however, a comprehensive investigation of the stability of their CD complexes has not been performed yet. To characterize the enantioselective complex formation, a systematic experimental design was developed in which a total number of 40 neutral, positively, and negatively charged CD derivatives were screened by affinity capillary electrophoresis and compared according to their cavity size, substituent type, and location. The functional groups responsible for the favorable interactions were identified in the case of para-substituted cathinone analog mephedrone, flephedrone, and 4-methylethcathinone (4-MEC) and in the case of 3,4-methylendioxy derivative butylone and methylenedioxypyrovalerone (MDPV). The succinylated-β-CD and subetadex exhibited the highest complex stabilities among the studied drugs. The complex stoichiometry was determined using the Job\'s plot method, and the complex structures were further studied using ROESY NMR measurements. The results of our enantioselective complex formation study can facilitate chiral method development and may lead to evaluate potential CD-based antidotes for cathinone analogs.

The emergence and mutation of pathogenic viruses have been occurring at an unprecedented rate in recent decades. The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed into a global public health crisis due to extensive viral transmission. In situ RNA mapping has revealed angiotensin-converting enzyme 2 (ACE2) expression to be highest in the nose and lower in the lung, pointing to nasal susceptibility as a predominant route for infection and the cause of subsequent pulmonary effects. By blocking viral attachment and entry at the nasal airway using a cyclodextrin-based formulation, a preventative therapy can be developed to reduce viral infection at the site of entry. Here, we assess the safety and antiviral efficacy of cyclodextrin-based formulations. From these studies, hydroxypropyl beta-cyclodextrin (HPBCD) and hydroxypropyl gamma-cyclodextrin (HPGCD) were then further evaluated for antiviral effects using SARS-CoV-2 pseudotypes. Efficacy findings were confirmed with SARS-CoV-2 Delta variant infection of Calu-3 cells and using a K18-hACE2 murine model. Intranasal pre-treatment with HPBCD-based formulations reduced viral load and inflammatory signaling in the lung. In vitro efficacy studies were further conducted using lentiviruses, murine hepatitis virus (MHV), and influenza A virus subtype H1N1. These findings suggest HPBCD may be used as an agnostic barrier against transmissible pathogens, including but not limited to SARS-CoV-2.

This study investigates the complexation of mefloquine hydrochloride by cyclodextrins to improve its solubility in order to design an oral solution. This approach may enhance the effectiveness of mefloquine, a drug which can be used for malaria prophylaxis and treatment in children. Mefloquine hydrochloride\'s solubility was assessed in different buffer solutions, and its quantification was achieved through high-performance liquid chromatography. The complexation efficiency with cyclodextrins was evaluated, and nuclear magnetic resonance (NMR) methods were employed to determine the interactions between mefloquine and cyclodextrins. Mefloquine\'s solubility increased when combined with hydroxypropyl-β-cyclodextrin (HP-β-CD) and randomly methylated β-cyclodextrin (RAMEB), with RAMEB being more effective. The drug\'s solubility varied across different pH buffers, being higher in acidic buffers. Interestingly, mefloquine\'s solubility decreased with a citrate buffer, possibly due to precipitation. The NMR studies highlighted non-covalent interactions between RAMEB, HP-β-CD, and mefloquine, explaining the solubilizing effect via complexation phenomena. Furthermore, the NMR experiments indicated the complexation of mefloquine by all the studied cyclodextrins, forming diastereoisomeric complexes. Cyclodextrin complexation improved mefloquine\'s solubility, potentially impacting its bioavailability.

Cyclodextrins (CDs) constitute a class of cyclic oligosaccharides that are well recognized and largely applied in the drug delivery field, thanks to their biocompatibility, low cost, and the possibility to be derivatized in order to tune and optimize the complexation/release of the specific drug. The conformational flexibility of these systems is one of their key properties and requires a cost-effective methodology to be studied by combining the accuracy of results with the possibility of exploring a large set of conformations. In the present paper, we have explored the conformational potential energy surface of the monomers and dimers of α-, β-, and γ-cyclodextrins (i.e., 6, 7, and 8 monomeric units, respectively) by means of fast but accurate semiempirical methods, which are then refined by state-of-the-art DFT functionals. Moreover, the crystal structure is considered for a more suitable comparison with the IR spectrum experimentally recorded. Calculations are carried out in the gas phase and in water environments, applying both implicit and explicit treatments. We show that the conformation of the studied molecules changes from the gas phase to the water, even if treated implicitly, thus modifying their complexation capability.

In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to β-CD, called β-CD(A), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): β-CD(A) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L3-edge EXAFS spectrum revealed 5 Gd-O (4 COO- and 1 H2O) and 4 Gd-N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02 Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)], also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd-N distance is shorter in the Gd(III): β-CD(A) (1:1) complex, indicating stronger Gd-N bonding and stronger Gd(III) complex formation than with the DOTA4- ligand. This is consistent with the lower free Gd3+ concentration found previously for the Gd(III): β-CD(A) (1:1) complex than for the [Gd(DOTA)(H2O)]- complex, and shows its potential as an MRI probe. EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified β-cyclodextrin: Gd(III) 1:1 complex, [Gd(LH4)]7-, in aqueous solution than for the clinically used MRI contrast agent Na[Gd(DOTA)(H2O)].

A class of cyclodextrin (CD) dimers has emerged as a potential new treatment for atherosclerosis; they work by forming strong, soluble inclusion complexes with oxysterols, allowing the body to reduce and heal arterial plaques. However, characterizing the interactions between CD dimers and oxysterols presents formidable challenges due to low sterol solubility, the synthesis of modified CDs resulting in varying number and position of molecular substitutions, and the diversity of interaction mechanisms. To address these challenges and illuminate the nuances of CD-sterol interactions, we have used multiple orthogonal approaches for a comprehensive characterization. Results obtained from three independent techniques - metadynamics simulations, competitive isothermal titration calorimetry, and circular dichroism - to quantify CD-sterol binding are presented. The objective of this study is to obtain the binding constants and gain insights into the intricate nature of the system, while accounting for the advantages and limitations of each method. Notably, our findings demonstrate ∼1000× stronger affinity of the CD dimer for 7-ketocholesterol in comparison to cholesterol for the 1:1 complex in direct binding assays. These methodologies and findings not only enhance our understanding of CD dimer-sterol interactions, but could also be generally applicable to prediction and quantification of other challenging host-guest complex systems.